Antipsychotic treatment based on DRD2 or ANKK1 SNP genotype

ABSTRACT

The present invention relates to the treatment of an individual with an antipsychotic based on individual&#39;s genotype at one or more single nucleotide polymorphism (SNP) associated with the dopamine receptor D2 (DRD2) and/or ankyrin repeat and kinase domain containing 1 (ANKK1) genes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/178,934, filed 15 May 2009, which is herebyincorporated herein.

BACKGROUND OF THE INVENTION

Schizophrenia affects approximately 1% of the population. It ischaracterized by the presence of positive symptoms (unusual thoughts orperceptions, including hallucinations and delusions), negative symptoms(social withdrawal, lack of pleasure in everyday life), and impairedcognitive functions (verbal memory, information processing). Suchsymptoms may be indicative of other disorders, such as, for example,bipolar disorder.

A number of antipsychotic drugs have been approved to treatschizophrenia. However, patient response to treatment remains highlyvariable, and the discontinuation rate with antipsychotic treatment ishigh. No single antipsychotic agent offers optimal effect for everypatient with schizophrenia. Few data are available to guide cliniciansand patients in the selection of the most appropriate medication and inthe improvement of treatment specificity for an individual patient.Pharmacogenomics provides the opportunity to discover genetic markerspredictive of response. Knowing how a patient with schizophrenia mightrespond to a particular therapy based on his or her genetic makeup mayenable clinicians to select the most optimal drug and dosage with lesstrial and error.

SUMMARY OF THE INVENTION

The present invention relates to the treatment of an individual with anantipsychotic based on individual's genotype at one or more singlenucleotide polymorphism (SNP) associated with the dopamine receptor D2(DRD2) and/or ankyrin repeat and kinase domain containing 1 (ANKK1)genes, as well as prediction of the efficacy of treating with anantipsychotic an individual having one or more SNP genotypes associatedwith relatively greater antipsychotic treatment efficacy.

One aspect of the invention provides a method of predicting the efficacyof using iloperidone in the treatment of at least one psychotic symptomin an individual, the method comprising: determining the individual'sgenotype at the rs1800497 single nucleotide polymorphism (SNP); and inthe case that the individual's genotype at the rs1800497 SNP locus isassociated with relatively greater iloperidone efficacy, predicting thattreating the individual with iloperidone will be efficacious.

Another aspect of the invention provides a method of predicting theefficacy of using iloperidone in the treatment of at least one psychoticsymptom in an individual, the method comprising: determining theindividual's genotype at the rs2283265 single nucleotide polymorphism(SNP); and in the case that the individual's genotype at the rs2283265SNP locus is associated with relatively greater iloperidone efficacy,predicting that treating the individual with iloperidone will beefficacious.

Still another aspect of the invention provides a method of predictingthe efficacy of using iloperidone in the treatment of at least onepsychotic symptom in an individual, the method comprising: determiningthe individual's genotype at the rs1076560 single nucleotidepolymorphism (SNP); and in the case that the individual's genotype atthe rs1076560 SNP locus is associated with relatively greateriloperidone efficacy, predicting that treating the individual withiloperidone will be efficacious.

Yet another aspect of the invention provides a method of administeringan effective dose of iloperidone to an individual, the methodcomprising: determining for the individual a baseline dose ofiloperidone; determining the individual's genotype at the rs1800497single nucleotide polymorphism (SNP); and in the case that theindividual's genotype at the rs1800497 SNP locus is associated withrelatively greater iloperidone efficacy, administering to the individualan effective does of iloperidone that is less than the baseline dose ofiloperidone.

Another aspect of the invention provides a method of treating a patientsuffering a psychotic disorder, the method comprising: determining thepatient's genotype at one or more of the following genetic loci:rs1800497, rs1799978, rs1799732, rs2283265, rs1076560, and rs6275; andin the case that the patient's genotype at said one or more genetic lociis associated with relatively greater iloperidone efficacy,administering to the individual an effective dose of iloperidone that isless than would otherwise be administered.

Still another aspect of the invention provides a method of treating apatient suffering a psychotic disorder, the method comprising:determining the patient's genotype at one or more of the followinggenetic loci: rs1800497, rs1799978, rs1799732, rs2283265, rs1076560, andrs6275; and in the case that the patient's genotype at said one or moregenetic loci is associated with relatively lesser iloperidone efficacy,administering to the individual an effective dose of iloperidone that isgreater than would otherwise be administered or administering to thepatient a drug other than iloperidone.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features of the invention will be more readilyunderstood from the following description of the various aspects of theinvention taken in conjunction with the accompanying drawings thatdepict various embodiments of the invention, in which:

FIG. 1 shows the locations of SNPs associated with the ANKK1 and DRD2genes;

FIGS. 2 and 3 show the statistical significance of various SNPs in thewhite and black populations, respectively; and

FIG. 4 shows the changes in PANSS-T based on Taq1A genotype in white andblack populations.

It is noted that the drawings are not to scale and are intended todepict only typical aspects of the invention and therefore should not beconsidered as limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone) is disclosed in U.S. Pat. RE39198,which is incorporated herein by reference. Active metabolites ofIloperidone are useful in the present invention. See, e.g., WO03020707,which is incorporated herein by reference. Iloperidone metabolitesinclude:4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone,4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol,4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxy-α-methylbenzenemethanol,1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone,and1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.See, U.S. RE39198, WO93/09276 and WO95/11680, which are incorporatedherein by reference.

An effective amount of iloperidone or an active metabolite thereof maybe administered to a subject animal (typically a human but otheranimals, e.g., farm animals, pets and racing animals, can also betreated) by a number of routes. An effective amount is an amount thatduring the course of therapy will have a preventive or ameliorativeeffect on a psychotic disorder, such as schizophrenia, or a symptomthereof, or of bipolar disorder. An effective amount, quantitatively,may vary, depending upon, for example, the patient, the severity of thedisorder or symptom being treated, and the route of administration.

It will be understood that the dosing protocol including the amount ofiloperidone or an active metabolite thereof actually administered willbe determined by a physician in the light of the relevant circumstancesincluding, for example, the condition to be treated, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms. Patients should of course bemonitored for possible adverse events.

For therapeutic or prophylactic use, iloperidone or an active metabolitethereof will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in association with a solid or liquid pharmaceuticallyacceptable carrier and, optionally, with pharmaceutically acceptableadjuvants and excipients employing standard and conventional techniques.

Pharmaceutical compositions useful in the practice of this inventioninclude suitable dosage forms for oral, parenteral (includingsubcutaneous, intramuscular, intradermal and intravenous), transdermal,bronchial or nasal administration. Thus, if a solid carrier is used, thepreparation may be tableted, placed in a hard gelatin capsule in powderor pellet form, or in the form of a troche or lozenge. The solid carriermay contain conventional excipients such as binding agents, fillers,tableting lubricants, disintegrants, wetting agents and the like. Thetablet may, if desired, be film coated by conventional techniques. If aliquid carrier is employed, the preparation may be in the form of asyrup, emulsion, soft gelatin capsule, sterile vehicle for injection, anaqueous or non-aqueous liquid suspension, or may be a dry product forreconstitution with water or other suitable vehicle before use. Liquidpreparations may contain conventional additives such as suspendingagents, emulsifying agents, wetting agents, non-aqueous vehicle(including edible oils), preservatives, as well as flavoring and/orcoloring agents. For parenteral administration, a vehicle normally willcomprise sterile water, at least in large part, although salinesolutions, glucose solutions and like may be utilized. Injectablesuspensions also may be used, in which case conventional suspendingagents may be employed. Conventional preservatives, buffering agents andthe like also may be added to the parenteral dosage forms. Thepharmaceutical compositions may be prepared by conventional techniquesappropriate to the desired preparation containing appropriate amounts ofiloperidone or an active metabolite thereof. See, for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., 17th edition, 1985.

In making pharmaceutical compositions for use in the invention, theactive ingredient(s) will usually be mixed with a carrier, or diluted bya carrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the active ingredient. Thus, thecomposition can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions andsterile packaged powders.

Some examples of suitable carriers and diluents include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage form” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired prophylactic or therapeutic effect over the courseof a treatment period, in association with the required pharmaceuticalcarrier.

Iloperidone and its active metabolites can also be formulated in acontrolled release form, e.g., delayed, sustained, or pulsatile release.

Various formulations and methods of administering iloperidone and/or itsderivatives have been described. For example, PCT Publication No. WO2004/006886 A2 describes an injectable depot formulation comprisingiloperidone crystals, microencapsulated depot formulations ofiloperidone and a polyglycolide polylactide glucose star polymer aredescribed in U.S. 20030091645, and methods for the administration ofiloperidone directed toward, inter alia, eliminating or minimizing theprolongation of a corrected electrocardiographic QT (QTc) intervalassociated with increased concentrations of iloperidone or iloperidonederivatives are described in PCT Publication No. WO 2006/039663 A2, allof which are incorporated herein by reference.

Whole Genome Association Study

Several single nucleotide polymorphisms (SNPs) were found to beassociated with improved response to iloperidone following a wholegenome association study (WGAS) performed in a phase III clinical trialof iloperidone. The clinical trial evaluated the efficacy of iloperidonein treating patients with diagnosed schizophrenia. The study, itsresults, and the inferences drawn therefrom are described below.

Methods

A four-week, randomized, double-blind, placebo- andziprasidone-controlled, multicenter inpatient phase III clinical trialof iloperidone was conducted, including 409 individuals, to assess theefficacy of iloperidone, as measured by changes in the Positive andNegative Syndrome Scale Total (PANSS-T). Six SNPs were analyzed,including two intronic SNPs and one exonic SNP, as shown in FIG. 1, aswell as Table I below.

TABLE 1 DRD2/ANKK1 Polymorphisms Analyzed SNP location rs1799978 (−241A/G) upstream rs1799732 (−141 C Ins/Del) upstream rs2283265 Intron 5rs1076560 Intron 6 rs6275 (His313His) Exon 7 rs1800497 (Taq1A)downstream

The rs179978 SNP is believed to regulate DRD2 expression levels andstriatal receptor density. Some patients carrying the -241 A alleleshowed a greater response when treated with risperidone than didpatients carrying the -241G allele.

The rs1799732 SNP is also believed to regulate DRD2 expression levelsand striatal receptor density. Schizophrenic patients carrying the -141CDel allele have been reported to take a significantly longer time torespond to antipsychotics (risperidone, olanzapine, and chlorpromazine)than patients carrying the -141C Ins allele.

Alternative splicing of exon 6 of the DRD2 gene yields at least threeisoforms: short (DRD2S), long (DRD2L), and longer. The rs2283265 andrs1076560 SNPs decrease expression of DRD2S relative to DRD2L.

Schizophrenic patients with a C/C genotype for the rs6275 SNP have beenreported to exhibit greater improvement when treated with clozapine,haloperidol, or risperidol than patients with a non-C/C genotype.

The rs1800497 polymorphism, originally assigned to DRD2, has since beenshown to be located within exon 8 of the ankyrin repeat and kinasedomain containing 1 (ANKK1) gene. The A1 allele has been linked to lowstriatal dopamine D2 receptor density in healthy individuals and may beassociated with increased activity of the striatal L-amino aciddecarboxylase, the final enzyme in the biosynthesis of dopamine. The A2allele has been associated with schizophrenia. In some populations, A2homozygotic patients exhibited significantly higher antipsychoticresponse than did heterozygotic patients. In another population, the A1allele was shown to be in linkage disequilibrium with the minor alleleof the rs2283265 and rs1076560 SNPs described above.

Patients, all diagnosed with an acute exacerbation of schizophrenia,were randomly assigned to one of three groups. A first group (n=218)received 24 mg/d (12 mg bid) of iloperidone, a second group (n=103)received 160 mg/d (80 mg bid) ziprasidone, and a third group (n=105)received a placebo. Efficacy was measured by a change from baseline inPANSS-T score.

Results

None of the six SNPs analyzed was associated with baseline PANSS-T inthe general study population or in the white or black subpopulations.

The Taq1A polymorphism exhibited the most statistically significanteffect at day 14 in the white subpopulation. See FIG. 2, cf. FIG. 3.Statistically significant effects were also observed with this SNP atdays 7, 10, and 21. See FIG. 4. At day 14, the mean change in PANSS-Tfor non-A1/A2 patients was −12.7 (±2.1) and for A1/A2 patients was −2.1(±2.7), resulting in a p value of 0.003).

The intronic rs2283265 and rs1076560 SNPs were also significantlyassociated with iloperidone response in the white subpopulation at day14 (p=0.01 and p=0.05, respectively). White patients carrying a non-G/Tgenotype for rs2283265 higher efficacy (PANSS-T mean change of −11.8(±2.0)) than white patients carrying the G/T genotype (PANSS-T meanchange of −2.4 (±3.0)) (p=0.01).

It should be noted that the differences in p-values observed among theidentified subpopulations (White, Black, and Asian) are not taken tosuggest that the rs1800497 polymorphism is predictive of iloperidoneefficacy among those groups exhibiting non-statistically significantp-values. The p-value for the overall population is statisticallysignificant and the lack of statistically significant p-values amongsome subpopulations may be attributed to the sample size of thesubpopulation, differences in allele frequencies, or both.

The results above may be employed in predicting the efficacy ofiloperidone in the treatment of a patient based on the patient'sgenotype at one or more of the SNPs above.

The results may also be employed in determining an effective dose ofiloperidone for a patient. For example, the recommended target dosage ofiloperidone (FANAPT™) tablets is 12 to 24 mg/day administered twicedaily. (The full prescribing information for FANAPT™ is herebyincorporated by reference.) This target dosage range is typicallyachieved by daily dosage adjustments, alerting patients to symptoms oforthostatic hypotension, starting at a dose of 1 mg twice daily, thenmoving to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily on days2, 3, 4, 5, 6, and 7 respectively, to reach the 12 mg/day to 24 mg/daydose range. Determining whether a patient carries a genotype associatedwith relatively greater iloperidone efficacy, such a dosage adjustmentregimen may be maintained and/or the maximum dosage may be halted at 12mg/day (6 mg twice per day). If, on the other hand, it is determinedthat the patient carries a genotype associated with relatively lesseriloperidone efficacy, the dosage adjustment regimen may begin with ahigher initial dosage (e.g., 2 mg/day rather than 1 mg/day) and/or themaximum dosage may be halted at 24 mg/day (12 mg twice per day). Inother cases, an alternative treatment (e.g., a non-iloperidone treatmentor a treatment including co-administration of iloperidone and at leastone other compound) may be pursued.

These results may also be used in treating a patient suffering from apsychotic disorder, such as schizophrenia. For example, if it isdetermined that the patient carries a genotype associated withrelatively greater iloperidone efficacy at one or more of the six SNPsdescribed above, the patient may be administered an effective dose ofiloperidone that is less than a dose that would otherwise beadministered to the patient (i.e., less than a dose that would beadministered to a patient not carrying a genotype associated withrelatively greater iloperidone efficacy and/or less than a dose thatwould be administered to a patient whose genotype(s) had not beendetermined).

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof the invention as defined by the accompanying claims.

What is claimed is:
 1. A method of determining an effective dose ofiloperidone in the treatment of at least one psychotic symptom in anindividual, the method comprising: determining, or having determined,from a biological sample of the individual, the individual's genotype atthe rs1800497 single nucleotide polymorphism (SNP); in the case that theindividual's genotype at the rs1800497 SNP locus is non-A1/A2:administering to the individual a first starting dose of iloperidone;and gradually increasing the dose of iloperidone administered to theindividual to a first effective dose; and in the case that theindividual's genotype at the rs1800497 SNP locus is A1/A2: administeringto the individual a second starting dose of iloperidone; and graduallyincreasing the dose of iloperidone administered to the individual to asecond effective dose, wherein the second starting dose is about twicethe first starting dose and the second effective dose is about twice thefirst effective dose.
 2. A method of administering an effective dose ofiloperidone to an individual, the method comprising: determining, orhaving determined, from a biological sample of the individual, theindividual's genotype at the rs1800497 single nucleotide polymorphism(SNP); in the case that the individual's genotype at the rs1800497 SNPis non-A1/A2, administering to the individual a first effective dose ofiloperidone that is less than or equal to 12 mg/day; and in the casethat the individual's genotype at the rs1800497 SNP is A1/A2,administering to the individual a second effective dose of iloperidonethat is about twice the first effective dose.
 3. The method of claim 2,wherein: the second effective dose of iloperidone is greater than 12mg/day.
 4. The method of claim 3, wherein the second effective dose ofiloperidone is greater than or equal to 16 mg/day.
 5. The method ofclaim 4, wherein the second effective dose of iloperidone is greaterthan or equal to 20 mg/day.
 6. The method of claim 5, wherein the secondeffective dose of iloperidone is 24 mg/day.
 7. The method of claim 2,further compromising: administering to the individual at least one othercompound in combination with the second effective dose of iloperidone.8. The method of claim 1, wherein the first effective dose is less thanor equal to 12 mg/day.
 9. The method of claim 1, wherein graduallyincreasing the dose of iloperiodone administered to the individual tothe first effective dose includes: increasing the dose from the firststarting dose of 1 mg twice daily to a first intermediate dose of 2 mgtwice daily.
 10. The method of claim 9, wherein gradually increasing thedose of iloperidone administered to the individual to the firsteffective dose further includes: increasing the dose from the firstintermediate dose to a second intermediate dose of 4 mg twice daily. 11.The method of claim 10, wherein gradually increasing the dose ofiloperidone administered to the individual to the first effective dosefurther includes: increasing the dose from the second intermediate doseto the first effective dose of 6 mg twice daily.
 12. The method of claim1, wherein gradually increasing the dose of iloperidone administered tothe individual to the first effective dose includes alerting theindividual to symptoms of orthostatic hypotension.
 13. The method ofclaim 1, wherein gradually increasing the dose of iloperidoneadministered to the individual to the second effective dose includesalerting the individual to symptoms of orthostatic hypotension.
 14. Themethod of claim 2, further comprising: alerting the individual tosymptoms of orthostatic hypotension.